Alzheimer?s disease (AD) is a neurodegenerative disorder characterized by dysfunction and deterioration of neurons resulting in loss of memory and progressive cognitive decline. Current treatments are aimed only at symptommanagement.Threebarrierstoeffectivetherapeuticdevelopmentinclude:1)alackofdefinitionofthe heterogeneityofADpathogenesis,2)alackofhighlypredictivebiomarkerstofacilitateearlyintervention,and 3) a need to identify pathways involved in cognitive decline and AD that can be targeted for therapeutic intervention.Weareusinginducedpluripotentstemcell(iPSC)technologycoupledtocomprehensivestudiesof patient populations to interrogate the cellular and molecular mechanisms underlying AD in an effort to break downthesebarriers.WeproposethatthereexistmultipleformsofADthathavedifferentunderlyingcauses,and that multiple therapeutic interventions may be needed to address disparate etiologies. Through other funding sources,wehavegenerated50iPSClinesfromtwocohorts,theReligiousOrderStudy(ROS)andtheMemory and Aging Project (MAP). Here, we propose to study these lines, where we focus upon three categories of subjects that lie on the extreme ends of the pathological spectrum: 1) no brain pathology, not cognitively impaired,2)highpathologynotcognitivelyimpaired,and3)highpathology,lateonsetAlzheimer?sdisease.In addition, we have generated and/or collected iPSC lines from familial AD subjects, which will be analyzed in parallel. Using iPSC derived neurons, astrocytes, and microglia from 60 human subjects, we will measure AD relevant outcomes (A?, p-tau, cytokines/chemokines) in Aim 1 and acquire unbiased transcriptomic and proteomicdatainAim2.Thesedatawillbeintegratedwithclinicaldata,neuropathologydata,andgeneticdata acquiredfromthesamesubjectsfromwhomthecellswerederivedusingmultiplecomputationalapproaches. Wehypothesizethat:1)Somepathologicalfindingsinthepostmortembraincanbepredictedbyinvitrocellular assaysoniPSCderivedneuronsandglia(Aim1),and2)Bothneuropathologyandcognitivedeclineinsome human subjects can be predicted by transcriptomic and proteomic level network analyses of iPSC derived neuronsandglia.Preliminarydatafrom12linessupportsthepremisethatiPSC-derivedcellswillcapturecertain cellandmolecularsignaturesthatdefinesubgroupsofagedadults.Datafromall50ROS/MAPlinesandEOAD models generated in aims 1 and 2 will provide a well-defined framework to address mechanistic questions regarding AD. In Aim 3 we will leverage the deeply characterized set of iPSC-derived cultures to address the hypothesisthatdysregulatedinositol5-phosphataseactivityofINPP5D(SHIP1)and/orINPPL1(SHIP2)leads toanelevatedriskforLOADinasubsetofsubjects.Throughthesestudies,weaimtoevaluatewhetheriPSC- derivedcellscanactasadiagnosticorprognostictoolforcognitivedeclineandAD,andbegintoaddressthe cellandmolecularmechanismsunderlyingheterogeneityinLOAD.